Of the 1,870 ongoing cancer clinical trials in the
world, 531 are phase I clinical trials designed to verify the safety of
experimental cancer treatments and procedures for use in humans.
As these trials may not directly benefit potential
participants, it is especially important that cancer patients are well informed
of the potential risks, potential benefits, medical procedures, and time
commitments involved in the study before they agree to participate.
The health care professionals who are involved in the process
of informed consent are charged with the tremendous responsibility of ensuring
that potential trial participants understand the different aspects of the
Christopher Daugherty tackles these complex issues in his
article entitled "Informed Consent, the Cancer Patient, and Phase I
Clinical Trials" in Ethical Issues in Cancer Patient Care (Kluwer Academic
Publishers, 2000). In this chapter, he elucidates the history and evolution of
informed consent in the last few decades.
Daugherty uses this history as a basis for a discussion about
consenting patients in phase I cancer clinical trials and presents
thought-provoking conclusions about how much trial participants truly
understand about their participation.
Experts in medical ethics grapple with the task of establishing
a definition of informed consent, a concept that continues to evolve as
clinical research progresses in new directions. Daugherty generally defines
informed consent as a "process of communication" between a potential
participant and an investigator regarding the experimental treatment or
procedure to be examined in a research study.
Most health care professionals incorporate the following five
elements into this communication process with the patient:
Disclosure involves informing patient of the potential risks
and benefits of the trial procedures and alternative methods of treatment for
their condition besides participation in the study. This aspect of informed
consent also includes conveying the experimental nature of the research to the
patient and emphasizing the participant’s freedom to withdraw from the trial
at any point without jeopardizing his or her future access to medical care.
Comprehension, the second element of a legally valid informed
consent, requires that patients have a "substantial" understanding of
the information disclosed to them by the investigator.
The issue of comprehension in informed consent has been
surrounded by controversy in the last few years. Certain health care
professionals believe that patients should understand all of the information
presented to them, and they want to disclose as much information as possible to
Other health care practitioners believe that "there is no
guarantee that everyone’s interests and needs [would] be served" should
this approach be used by those involved in getting informed consent from
patients. Faden and Beauchamp believe that such disclosures would be too
long and would be ineffective in achieving substantial patient understanding.
Rather, they would like to refocus the discussions on informed consent and
devise ways to create more effective communication between the investigator and
The last three aspects of informed consent relate to patients’
ability to make an autonomous, thoughtful decision about their participation in
a research study. While potential participants are evaluated for their
emotional and mental capacity to give informed consent, they should also be
free from coercion or influence from health care practitioners who may have a
"conflict of interest" as health care workers and investigators in
Origins of Informed Consent
In elucidating the origins of the process of informed consent,
Daugherty notes that the concept of informed consent has often been erroneously
attributed to the Nuremberg Code. He states that the Nuremberg Code
specifically responds to the crimes against humanity perpetrated on people in
Nazi concentration camps during World War II. He points out that the Nazi
physicians who committed these atrocities did not have their victims’
therapeutic benefit in mind as they conducted their research.
Instead, Daugherty traces the first legal use of the term
"informed consent" to a California Supreme Court case in 1957. The
court ruled that no patient can be subjected to "medical intervention
without having been given prior ‘informed consent.’"
Daugherty also notes that in a 1947 letter, the Atomic Energy
Commission stated the need for "informed consent" in response to an
investigator’s request to report declassified data from federally sponsored
radiation research on cancer patients. Thus, the concept of informed consent
began to permeate the field of medical research in the 1950s and 1960s.
The concept of informed consent was only in its infancy when
Harvard anesthesiologist Henry Beecher published an important article in the
New England Journal of Medicine in 1966. In this groundbreaking article,
Beecher detailed 22 clinical trials carried out in the 1950s and 1960s that
violated the rights of human subjects. The trial designs and procedures Beecher
described jeopardized the health of the participants, who were often completely
unaware of the risks such biomedical research posed to them.
Two of the studies described by Beecher involved the use of
cancer patients in cancer clinical research. At one study site, later
identified as the Jewish Chronic Disease Hospital, hospitalized patients were
injected with malignant cells from cancer patients to evaluate the body’s
immune response to cancer. The participants were elderly and debilitated
patients without cancer. They were told that they would be injected with
"some cells." The word "cancer" was never mentioned.
Another study described by Beecher involved a mother who
consented to a transplant of melanoma from her terminally ill daughter ".
. .in the hope that the production of tumor antibodies might be helpful in the
treatment of the cancer patient." The researchers intended to withdraw
serum from the mother and administer it to the patient. Unfortunately, the
daughter died 1 day after the transplantation was complete. The tumor implant
was removed from the mother 24 days later. The mother died about 1 year later
from diffuse melanoma that had metastasized from the tumor implant.
Beecher’s work on these two cases and the 20 other studies
described in his article shocked the medical community, leading to tighter
regulations in government-sponsored clinical research in the 1960s and 1970s.
Daugherty notes that other such discussions ultimately resulted
in the creation of the National Commission for the Protection of Human Subjects
in Biomedical and Behavioral Research. This committee’s recommendations led
to the measures that are currently used to protect the rights of research
subjects: the formal institutional review process and the use of informed
What Motivates Patients
As a large number of clinical trials relate to cancer care,
Daugherty focuses the rest of his chapter on analyzing the factors that
motivate cancer patients to participate in studies that do not offer them a
direct therapeutic benefit.
Specifically, Daugherty addresses debates about the level of
patient understanding of clinical trials by examining studies that investigated
the motivations and perceptions of participants in phase I cancer clinical
Dr. Sjoerd Rodenhuis and his colleagues in the Netherlands
conducted the first of these studies. They explored the motives of 48 patients
with advanced-stage cancer who agreed to participate in a phase I clinical
trial. The informed consent process for this study involved three different
sessions that included the patient, the family, and health care
After these three sessions, 10 cancer patients who agreed to
participate in the study were separately interviewed to determine how well they
recalled the information disclosed in the informed consent process, what
motivated them to participate in the trial, and whether they were content with
The investigators determined that eight of the 10 patients were
adequately informed. However, four of these eight patients appeared to have an
incomplete understanding of the intent of the trial, as they objected to being
considered the "subject of an experiment."
These four patients stated that potential therapeutic benefit
largely motivated them to participate in the study, and one other patient felt
similarly. The husbands of three patients strongly encouraged them to take part
in the study. In particular, the spouses urged these three patients to
"grab at their last straws."
The remaining two patients could not point to a specific
motivation and stated that they were complying with the expectations of their
It should be noted that seven of the 10 patients also
spontaneously stated during their treatment that they were interested in
furthering the progress of science.
Based on these data, the investigators concluded that along
with potential therapeutic benefit, influence from loved ones was a large
factor in motivating advanced cancer patients to participate in clinical
US Survey Study
Daugherty and his colleagues at the University of Chicago
designed and executed a similar pilot study in which they surveyed 30 cancer
patients who had agreed to participate in trials at that institution. Of the
patients surveyed, 85% cited "possible therapeutic benefit" as their
main motivation for participation in the trial; 11% said they participated
because of influence from or trust of physicians; and 4% said they were
pressured into participation by their families.
A full 93% of the patients stated that they understood all or
most of the information disclosed to them in the informed consent process.
However, only one third of this group was able to state the objective of the
trial, and only the more educated patients were able to state the general
purpose of phase I clinical trials.
This suggests that the level of the information presented in
the consenting process about the purpose of the study was inaccessible to many
Based on these findings, the authors concluded that while
altruistic feelings are present in the patients, their main motivation for
participation stems from the perceived prospect of potential therapeutic
benefit. In addition, Daugherty suggests that the patients capable of
understanding the idea of dose escalation may have ignored this information
because it was inconsistent with their hopes for potential therapeutic benefit.
Another interesting finding of this study was that many
patients stated that alternatives to participation in the trial were omitted
from the consenting process, although all written consent documents included
Daugherty believes that the patients’ hopes for therapeutic
benefit may reflect the beliefs of the physicians involved in the design and
execution of these trials. Their study also involved a survey of oncologists
involved in clinical trials. The oncologists were found to have high
expectations about the investigational agent’s potential therapeutic benefit
for trial participants.
Overall, the lack of patient comprehension about the objective
of the trial and the prevalence of potential perceived benefit of trial
participation suggest that further discussion of these issues is essential.
New Methods Needed
The results of these studies suggest that there is a
discrepancy between what cancer patients believe they understand based on
informed consent procedures and what they actually understand about the
clinical trial in which they participate.
To alleviate this problem and other difficulties in informed
consent procedures, Daugherty suggests that researchers explore novel ways of
obtaining informed consent. The author along with his collaborators recently
conducted a study of an approach termed "cohort-specific informed
consent," which involves a consent form that can be adjusted as a trial
Thus, while great progress in the fields of medical ethics and
clinical research has been made since the 1950s and 1960s, the discussion
surrounding the issue of informed consent remains quite active. Finding
solutions to these ethical issues is not trivial, and researchers should
continue to explore methods of refining this procedure to ensure that the
rights of patients remain well protected.
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